Organic Nanomedicine Containing Nonlinear Optical Chromophores for Ultrastable Photo-to-Heat Converting Theranostics in the Near-Infrared Window

doi:10.21203/rs.3.rs-1970104/v1

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Organic Nanomedicine Containing Nonlinear Optical Chromophores for Ultrastable Photo-to-Heat Converting Theranostics in the Near-Infrared Window

https://doi.org/10.21203/rs.3.rs-1970104/v1

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Background

Organic agents that are active in the near-infrared (NIR) bio-window for photo-to-heat energy-converting theranostics have attached much attention in cancer therapy. However, current organic NIR-absorbing agents are still suffering from the inefficient non-radiative decay or serious photobleaching under light irradiation. Herein, we design a convenient strategy to load a new kind of NIR-absorbing nonlinear optical (NLO) chromophores with a biocompatible polymer of methoxy poly(ethylene glycol)-poly(lactideco-glycolide) (mPEG-PLGA).

Results

The resulted NLO/PLGA nanoparticles showed excellent stability, high photothermal conversion efficiency (∼51.11%) and good photoacoustic performance. Moreover, in vitro anticancer experiments demonstrated that the NLO/PLGA nanoparticles possess a high PTT efficiency under NIR laser illumination.

Conclusions

This work thus provides an insight into the exploration of versatile organic NIR-absorbing nanoparticles toward future practical PTT application.

organic nanomedicine

near-infrared

photothermal

photoacoustic imaging

Near-infrared (NIR) photothermal agents, which can transfer absorbed NIR light into thermal energy by inhibiting the radiative relaxation of materials, have exhibit a great potential in photothermal therapy (PTT) (Bian et al. 2021; Chen et al. 2019; Han et al. 2021; Sun et al. 2021; Zhi et al. 2020). Various NIR photothermal agents have been developed, including carbon nanomaterials (Lan et al. 2017; Wu et al. 2013), gold nanostructures (Park et al. 2020; Vines et al. 2019), metal sulfide (Liu et al. 2015; Yong et al. 2015) or organic molecules (Cheng et al. 2012; Song et al. 2015). Among these photothermal agents, great interest has been placed on organic π-conjugated molecules owing to their excellent biocompatibility, high chemical versatility and accessible structural-property relationship. Some popularly-used organic molecules, including methylene blue (Narayanan et al. 2021) and indocyanine green (Yan et al. 2021), have been approved by the Food and Drug Administration (FDA) for clinical applications. Despite such promise, conventional organic molecules generally exhibit inefficient non-radiative decay, or serious photobleaching under light irradiation. Consequently, they are not ideal agents for PTT. New molecular design concept to advanced organic molecules with efficient non-radiative decay and stable photothermal capacity for PTT is highly desirable.

Nonlinear optical (NLO) chromophores, which consist of electron donor, π-conjugated bridge and strong electro-acceptor (D − π − A), are emerging as an important family of organic molecules (Antaris et al. 2017; Hu et al. 2009; Qian et al. 2008; Yang et al. 2018). Notably, through delicate structure tailoring, these NLO chromophores can exhibit an enhanced photo-to-thermal efficiency and high chemical stability, therefore offering great opportunity for PTT applications (Cai et al. 2017; Gao et al. 2019; Wang et al. 2018). Recently, our research group reported a NLO chromophore with a D-π-A structure to achieve PTT. The experiment results showed the prepared chromophore has a high photothermal conversion efficiency of ∼52.71% and excellent stability in physiological and high temperature environment (Feng et al. 2020). Though effective, the chromophore-based PTT operate under a 635 nm laser irradiation, which limits the PTT efficiency severely as a result of the shallow depth of tissue penetration. Considering the near infrared (NIR) light has deeper penetration and higher sensitivity and resolution over visible light, the synthesis of NLO chromophore-based nanostructures that can harvest NIR light is extremely attractive for PTT.

In this work, a new kind of NIR absorbing organic nanoparticles was developed by self-assembling thermal-stable NLO chromophores with an amphiphilic polymer of Methoxy poly(ethylene glycol)-poly(lactideco-glycolide) (mPEG-PLGA). The NLO chromophore with a D-π-A structure exhibits a broad and strong absorption at NIR region. After encapsulated into mPEG-PLGA, the as-obtained NLO/PLGA nanoparticles not only retained the high absorption at NIR region, but also possessed high stability when dispersed in water, PBS solution and DMEM solution. When under the NIR light irradiation, NLO/PLGA exhibited a high photothermal conversion efficiency of 51.11%, good photoacoustic (PA) performance and an excellent photothermal stability, thus having a great potential for non-invasive PA imaging and photothermal therapy of tumors.

Chemicals and materials

4-(dibutylamino)benzaldehyde, 2-Thiophenemethanol, and PPh₃HBr were purchased from the Sigma-Aldrich. Amphiphilic polymer mPEG (1000)-PLGA (1000) was bought from Shanghai Yare Biotech, Inc. Fetal bovine serum was provided by Wisent. Streptomycin and penicillin were obtained from Gibco. 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) was bought from Amresco. DMEM medium and PBS were purchased from Sangon Biotech. All chemicals were used as received without any further purification.

Instrumentations

Transmission electron microscopy (TEM) images of nanoparticles were taken on the JEM-2100 transmission electron microscope (JEOL, Japan). UV/Vis and fluorescent spectra were recorded on a Cary 5000 photo spectrometer (Agilent, USA) and Hitachi F-4600 spectrometer (Hitachi, JPN), respectively. PA signals and images were achieved via MOST (inVision 128, iThera Medical, GER). In vitro cytotoxicity assay was carried out on a ELx800t microplate reader (BioTek, America).

Synthesis of NLO chromophore

Synthetic details of NLO Chromophore are described as following.

Synthesis of compound 2: Compound 1 (3 g, 26 mmol) and PPh₃HBr (3 g, 9 mmol) were added into 50 mL CHCl₃. The mixture was refluxed for 3 hours, and CHCl₃ was removed. Then anhydrous ether was added and stirred. The ether solution was filtered to obtain the yellowish solid compound 2. M/z (EI): 438.42.

Synthesis of compound 4: Compound 2 (3.5 g, 16.6 mmol), compound 3 (1.8 g, 7.8 mmol), and NaH (3.5 g, 146 mmol) were dissolved in 100 mL absolute ether and stirred at room temperature for 48 hours. Then the mixture was slowly poured into 200 mL ice water. The solution was extracted with 150 mL ether, and dried with MgSO₄. The solution after separation was filtered, and the solvent was removed, and the product was separated and purified by column chromatography. M/z (EI): 313.371.

Synthesis of compound 5: To a solution of compound 4 (0.31 g, 1 mmol) in dry THF (20 mL) was added a 2.4 M solution of n-BuLi in hexane (0.6 ml, 1.5 mmol) dropwise at -78℃ under a N₂ atmosphere. After this the mixture was stirred at this temperature for 1 h, and the dry DMF (0.2 mL, 2.5 mmol) was introduced. The resulting solution was stirred for another 1 h at 78℃ and then allowed to warm up to room temperature. The reaction was quenched by water. THF was removed by evaporation. The residue was extracted with CH₂Cl₂. The organic layer was dried by MgSO₄ and concentrated in vacuo. The residue was purified by column chromatography on a silica gel (hexane-acetone, v/v, 10/1) to obtain a red product (yield: 82%). MALDI-TOF: m/z calcd for C₂₁H₂₇NOS: 341.18 [M]⁺; found: 341.502. ¹H NMR (400 MHz, CDCl₃) δ 9.84 (s, 1H), 7.21-7.00 (m, 6H), 6.63–6.25 (d, 2H), 3.88 (t, J = 6.6 Hz, 4H), 1.73–1.59 (m, 4H), 1.37 (d, J = 2.6 Hz, 4H), 0.83 (m, J = 5.2 Hz, 6H).

Synthesis of compound FTC-3f

The CF₃-TCF acceptor was synthesized according to the literature (Shao et al. 2016). A mixture of compound 5 (0.3 g, 0.9 mmol) and acceptor CF₃-TCF (0.6 g, 1.5 mmol) in ethanol (10 mL) was stirred at 75℃ for 2 h. After removal of the solvent, the residue was purified by column chromatography on a silica gel (hexane-ethyl acetate, v/v, 4/1). A dark solid was obtained (yield: 33%). MALDI-TOF: m/z calcd for C₄₁H₃₅FN₄OS₂: 720.22 [M]⁺; found: 720.877. ¹H NMR (400 MHz, CDCl₃) δ 7.89 (d, J = 15.4 Hz, 2H), δ 7.63 (d, J = 15.5 Hz, 2H), δ 7.48 (d, 2H), 7.26 (s, 1H), 7.24 (s, 1H), 7.14 (d, J = 8.6 Hz, 2H), 7.12–7.06 (d, 2H), 6.75 (d, J = 15.5 Hz, 1H), 6.71 (d, J = 8.7 Hz, 2H), 6.61 (d, J = 8.8 Hz, 2H), 4.27 (t, J = 6.6 Hz, 4H), 1.74 (m, J = 14.8, 8.3 Hz, 4H), 1.43 (m, J = 13.7, 6.2 Hz, 4H), 0.91 (m, 10.2, 6.8 Hz, 6H).

Synthesis of NLO/PLGA nanoparticles

The NLO/PLGA nanoparticles were prepared via a simple nanoprecipitation method. Typically, acetone solutions of NLO and mPEG-PLGA were quickly injected into deionized water under sonication (40 KHz). After sonicating for several minutes, the resulting NLO/PLGA nanoparticles were collected and redispersed in DI water.

Stability assessment of NLO/PLGA nanoparticles

The stability of nanoparticles was investigated by DLS. Typically, 200 µg of NLO/PLGA nanoparticles was dispersed uniformly in DI water, PBS or DMEM. At the given time periods (e.g., 1 D, 2 D, 3 D, 4 D, 5 D, 6 D, 7 D), the hydrodynamic diameter of the NLO/PLGA dispersion were recorded by DLS.

Photothermal evaluation of NLO/PLGA nanoparticles

Aqueous suspension of NLO/PLGA nanoparticles (200 µg/mL) was prepared and irradiated with a 750 nm NIR laser with different power densities (0.5, 0.6, 0.7, 0.8, 1.0 W/cm²). The temperature of NLO/PLGA solution was recorded using a thermal imaging camera (TiS65, Fluke, USA). Similarly, aqueous suspension of NLO/PLGA nanoparticles with different concentrations (0, 25, 50, 100 and 200 µg/mL) were prepared and irradiated with 750 nm NIR laser (1.0 W/cm²). The temperatures of solution were also carefully recorded in real-time. The temperature of deionized water was used as control. To further determine the photothermal conversion efficiency, NLO/PLGA aqueous solution was irradiated with 750 nm light for 10 min. Then the laser was shut off. The temperature changes during the laser-caused heating and cooling were recorded carefully. The photothermal conversion efficiency was calculated according to the previous reports.

MTT assay

DMEM medium containing 10% FBS, 100 units/ml aqueous penicillin G and 100 µg/mL streptomycin was prepared for cell culture. HeLa cells were seeded in a 96-well plate (8000 cells per well) and cultured at 37°C in a humidified atmosphere containing 21% O₂ and 5% CO₂ for 24 h. Then fresh medium containing at different concentrations of NLO/PLGA nanoparticles (0, 25, 50, 100, 200 µg/mL) was added. After 6 h incubation, the cells were washed thoroughly with PBS three times, and fresh DMEM was added into the wells. Then the cells were irradiated with NIR light for 10 min, followed another 24 h culture at 37°C. Finally, the viability of the HeLa cells was evaluated by a standard MTT test.

PA image of NLO/PLGA

Different concentrations of NLO/PLGA solution (0, 25, 50, 100, 200 µg/mL) were prepared and mixed with agarose for the in vitro PA imaging test. The PA signals and images were obtained via MOST (inVision 128, iThera Medical, GER).

Feasibility design of NLO chromophore is a useful strategy to obtain low-bandgap organic materials. In this work, we firstly synthesized a D − π − A type organic chromophore by using N,N-dibutylaniline as donor, planar thiophene ring as π-conjugation bridge and 2-dicyanomethylene-3-cyano-4-methyl-2,5-dihydrofuran (TCF) as acceptor. The synthesized chromophores, labeled as FTC, exhibit a broad and strong absorption between 600 ~ 700 nm (Scheme 1, Fig. 1a). In order to shift the absorption band from visible to NIR light region, 2-dicyanomethylene-3-cyano-4-methyl-5-trifluorometheyl-5-(5-phenylthiophene-2-yl)-2,5-dihydrofuran (CF₃-TCF) acceptor with strong electro-withdrawing ability is introduced into FTC chromophore. As expected, the resulted FTC-3f NLO chromophores showed a strong absorption in the spectral region of 600–1100 nm with a peak at ~ 780 nm (Fig. 1a), matching well with the biological window. Therefore, the FTC-3f NLO chromophores hold a great potential for NIR light-triggered theranostic bioapplications.

However, free NLO chromophores still face some formidable challenges as bioavailable agents, such as the hydrophobicity and short circulation half-life. To overcome these limitations, mPEG-PLGA, an FDA-approved polymer with PEG as the hydrophilic end and PLGA as the hydrophobic end (Feng et al. 2020; Liao et al. 2005), was used to encapsulate NLO chromophores through nanoprecipitation strategy. The schematic illustration of the encapsulation process is depicted in Fig. 1b, and the detailed procedure is presented in the Experimental Section. The as-synthesized NLO/PLGA nanoparticles showed well-defined spherical shape with an average diameter of 43.12 nm (Fig. 1c, d).

The ultraviolet-visible-NIR absorption spectrum of NLO/PLGA showed the characteristic absorption peak of NLO, indicating the successful encapsulation of NLO in the PLGA (Fig. 2a). Compared with free NLO chromophores, the absorption spectrum of NLO/PLGA has a remarkable broadening and redshift of NLO absorption band, mainly owing to the formation of J-aggregates during the nanoparticle formation. In addition, the stability of NLO/PLGA nanoparticles in PBS, pure water, and DMEM were investigated. The results show that NLO/PLGA nanoparticles are stable in PBS, pure water, and DMEM in one week (Fig. 2b).

The high absorption at NIR region and the ultrastability in PBS, pure water, and DMEM motivated us to investigate the NIR-driven photothermal property of NLO/PLGA nanoparticles. Firstly, the temperature elevations of NLO/PLGA aqueous solution (200 µg/mL) under a 750 nm NIR laser irradiation at varied power densities were recorded by a thermal imaging camera (TiS65, Fluke, USA). As shown in Fig. 3a, the solution temperature increased rapidly during under 750 nm laser irradiation, and the plateau temperature increased from 36 to 52°C as the irradiance power increased from 0.5 to 1.0 W/cm². Moreover, the temperature variation curves of different concentrations of NLO/PLGA were also conducted under 750 nm irradiation (1.0 W/cm²). As expected, the temperature increase of NLO/PLGA showed a concentration-dependent photothermal behavior (Fig. 3b). These results indicated the effective heat generation of NLO/PLGA under 750 nm irradiation.

As known, the photothermal stability of organic small molecules is an important but formidable challenge for PTT. To evaluate the photothermal stability of NLO/PLGA, the recycling temperatures of NLO/PLGA aqueous solution were recorded under 750 nm NIR irradiation for 10 min followed by cooling to room temperature. As presented in Fig. 3c, NLO/PLGA aqueous solution showed no obvious deterioration in photothermal capability after three irradiation/cooling cycles, illustrating the durable photothermal stability of NLO/PLGA under 750 nm NIR irradiation. Furthermore, through applying linear time data versus ln θ from the cooling stage (Fig. 3d), the photothermal conversion efficiency (η) of NLO/PLGA was calculated as 51.11%, indicating that NLO/PLGA can generate heat efficiently.

The in vitro cytotoxicity of NLO/PLGA against Hela cells was evaluated by a typical MTT assay. As presented in Fig. 4, treatment with NLO/PLGA decreased the cell viability slightly, demonstrating the low cell toxicity of these nanoparticles to MCF-7 cells. In contrast, the cells treated with NLO/PLGA following 750 nm NIR light irradiation (1 W/cm²) showed a significant cytotoxicity. The results confirmed the potential of NLO/PLGA as PTT anti-tumor agents. Moreover, the cell cytotoxicity increased obviously when increasing the concentrations of NLO/PLGA. When treated with 200 µg/mL of NLO/PLGA, a highest cell cytotoxicity of 80% was achieved.

Next, we investigated the PA property of NLO/PLGA nanoparticles. The PA intensity of NLO/PLGA aqueous solution is firstly measured in the spectral region of 680–850 nm. As shown in Fig. 5a, PA spectra of NLO/PLGA solution have a maximal intensity at about 680 nm. Then the PA images and the corresponding PA intensities of NLO/PLGA aqueous solution were further performed upon the excitation at 680 nm. The results in Fig. 5b,c showed that the PA signal enhanced linearly with increasing concentrations of NLO/PLGA aqueous solution from 0 to 200 µg/mL. Such a concentration-dependent PA imaging behavior is in accordance with the photothermal conversion property. These PA results reasonably reveal that NLO/PLGA nanoparticles can serve as efficient probes for PA imaging.

In summary, an efficient loading of NIR-absorbing NLO chromophores with a biocompatible polymer of mPEG-PLGA was achieved by an emulsion strategy to produce monodisperse NLO/PLGA nanoparticles. The NLO/PLGA possessed a broad and strong absorption at NIR region, and high stability when dispersed in water, PBS solution and DMEM solution. Moreover, under the NIR light irradiation, the NLO/PLGA exhibited a high photothermal conversion efficiency of 51.11%, good photoacoustic performance and excellent photothermal stability. These characteristics motivated us to investigate the in vitro antitumor activity. The results showed that the NLO/PLGA nanoparticles possess a high PTT efficiency. Therefore, this nanoparticle may provide a robust organic-nanoplatform for NIR-triggered cancer therapy.

Ethics approval and consent to participate

Human cell lines used in this study do not require ethics approval.

Consent for publication

Not applicable.

Availability of data and materials

The data obtained in this study are provided in this manuscript. Further additional data can be provided by corresponding authors upon request.

Competing interests

The authors declare that they have no competing interests.

Funding

This work was supported by the National Natural Science Foundation of China (No. 62175267), the Fundamental Research Funds for the Central Universities (2020MDJC13), the National Key Research and Development Program of China (Grant numbers: 2021YFB2800302 and 2021YFB2800604), and the Beijing Municipal Excellent Talents Foundation (2018000021223ZK45).

Author’s Contributions

All the authors contributed to the study conception and design. WF and SB contributed to material preparation. BL, WF, JG, ZL, ZC and SB conducted the experiments and collected the data. The first draft of the manuscript was written by BL and SB. All the authors reviewed the manuscript. All aspects of this study were supervised by SF and ZC. All authors read and approved the final manuscript.

Acknowledgements

Not applicable.

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Scheme 1 is available in the Supplemental Files section.

No competing interests reported.

Scheme1.png

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You are reading this latest preprint version

Organic Nanomedicine Containing Nonlinear Optical Chromophores for Ultrastable Photo-to-Heat Converting Theranostics in the Near-Infrared Window

Status:

Version 1

Abstract

Background

Results

Conclusions

Figures

Introduction

Experimental

Chemicals and materials

Instrumentations

Synthesis of NLO chromophore

Synthesis of compound FTC-3f

Synthesis of NLO/PLGA nanoparticles

Stability assessment of NLO/PLGA nanoparticles

Photothermal evaluation of NLO/PLGA nanoparticles

MTT assay

PA image of NLO/PLGA

Results And Discussion

Conclusion

Declarations

References

Scheme 1

Additional Declarations

Supplementary Files

Status:

Version 1